The compound 2,6-bis(diethanolamino)-4,8-dipiperidinopyrimido-[5,4-d]-pyrimidine, known as dipyridamole, is disclosed in U.S. Pat. No. 3,031,450, incorporated herein by reference. This compound has been successfully used as an active substance, such as a coronary vasodilator, for many years. The nature of the diseases or conditions treated with dipyridamole generally necessitates long-term or constant treatment. At the present time, dipyridamole is administered in tablets or capsules which are readily assimilable, that is, instantaneous, and must be administered three or four times a day.
A sustained release form of administration of dipyridamole would have the advantage of facilitating a reduction in the number of administrations per day, which would lead to better patient compliance. This is of significant importance with regard to long-term medication. Another advantage would be that delayed resorption would lead to more uniform levels in the blood, thus avoiding or minimizing blood level peaks, which can cause deleterious side effects, and would avoid sub-therapeutic levels of active substance, such as can occur with instantaneous forms during longer dosage intervals, for example, during the night. In other words, safety, compatability, and effectiveness of the preparation can be increased. Due to the obvious advantages of a sustained release form of dipyridamole, there have been previous efforts to develop such a form.
In the case of active substances which do not inherently have "sustained release properties" (for example, long biological half life or slow dissolution of crystalline active substances), sustained release forms can be obtained by, for example, the following known methods:
1. The active substance together with excipients is formulated so that it is released slowly, for example, by embedding it in a matrix which does not dissolve or dissolves only slowly; or PA1 2. The active substance together with the excipients is shaped into tablets, pellets, or the like, which are then provided with an insoluble coating which results in a slow release of the active substance. PA1 good pH-independent solubility in the entire gastro-intestinal tract, and PA1 no change in the resorption rate in the resorbable part of the gastro-intestinal tract.
Furthermore, coating agents for solid medicaments are known which consist of a cellulose derivative soluble in the intestine and of a cellulose derivative insoluble in digestive fluids, these components being present respectively in a mixture ratio of from 30 to 70 percent by weight to from 70 to 30 percent by weight, relative to one another. (See, for example, German Pat. No. 2,415,490.) Also known are oral sustained release forms with a linear release of active substance in the gastro-intestinal tract containing spheroid medicament particles which are provided with a dialysis membrane, as is disclosed in German Patent Application (DE-AS) No. 2,336,218. The membrane comprises (i) 15 to 70 percent by weight of a cellulose ether which is insoluble in the pH range of the gastro-intestinal tract and which is not decomposable enzymatically, with an alkoxy group content of from 43 to 50 percent by weight, and (ii) from 85 to 30 percent by weight of one or more compounds soluble only in the alkaline range of the intestinal tract, with a content of from 5 to 40 percent by weight of free carboxyl groups, such as, for example, hydroxypropyl methylcellulose phthalate.
In general, the following prerequisites apply to an active substance for the development of a sustained release form:
However, the physical and biochemical properties of dipyridamole are completely unsuitable for the typical development of a sustained release form. The biological half-life of dipyridamole is relatively short, that is, existing levels in the blood drop quickly, and a uniform dipyridamole level in the blood can be obtained only if active substance is constantly resorbed. Also, dipyridamole is soluble in aqueous medium only in the acid range; more specifically, above a pH of 4 the substance is practically insoluble in water. This means that dipyridamole can be dissolved only in the upper gastro-intestinal tract and consequently resorbed, whereas at the higher pH values occurring in the intestinal region it remains insoluble and is not resorbed.
Since the passage time through the stomach and the upper intestinal regions (with sufficiently acid pH) is relatively short (from about 0.5 to 2 hours), it is therefore difficult to achieve resorption over several hours. Moreover, the residence period in the stomach and in the various intestinal sections can vary considerably. Thus, naturally, in the case of a substance whose solubility depends on the pH, inter-individual and intra-individual variations of levels of active substance in the blood are extremely large when the substance preparation has a slow release, as is necessary with sustained release forms. Further, even if dipyridamole is introduced in dissolved form into various intestinal sections, the resorption rate decreases from the duodenum to the colon.
For the reasons above, the person skilled in the art would consider that an effective sustained release form of dipyridamole was precluded. This situation is also indicated by the presently known "sustained release forms" for dipyridamole. For example, one known form corresponding to known method 1 above comprises a sustained release form in which dipyridamole is pressed into matrix tablets with a swelling polyacrylic acid known by the tradename of Carbopol.RTM.. Determination of release in vitro has shown that this is a completely unsuitable sustained release form of dipyridamole since, with this form, dipyridamole can be dissolved only as long as the tablet is located in the acid medium of the stomach. When the matrix tablet reaches the small intestine, the release of active substance and, consequently the resorption, practically cease.
A recent sustained release form of dipyridamole in pellets, corresponding to known method 2, is described in French Patent Application No. 75 28462. The active substance is applied to inert starter cores which are subsequently provided with a sustained release coating. This publication discloses that pellets prepared according to the Eurand process, that is, enclosing pellets with a polymer coating, are suitable for providing a dipyridamole sustained release preparation. Testing has shown that with use of such pellets the levels of dipyridamole in the blood are distinctly lower in the beginning, as compared to the levels resulting from commercial, instantaneous forms such as coated tablets, and do not persist any longer. Hence, with use of such sustained release pellets, the release of active substance is impaired by about one-half with regard to relative bioavailability.
Thus, all hitherto known sustained release forms of dipyridamole have proven to be completely unsuitable, although in the case of other active substances very useful sustained release forms can be provided with the technologies employed. With the known sustained release forms, no more dipyridamole is dissolved out of the preparation after entry into the small intestine as a result of the increase in the pH value, the resorption of the active substance ceases, and it is impossible to achieve the desired long-lasting blood levels.